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Abstract

Background: Mobilization of stem/progenitors is regulated by the interaction between stromal cell-derived factor-1 (SDF-1) and its ligand, CXC chemokine receptor 4 (CXCR4). Statins have been suggested to ameliorate pulmonary arterial hypertension (PAH); however, the mechanisms involved, especially their effects on progenitors, are largely unknown. In the present study, we examined whether pravastatin ameliorates hypoxia-induced PAH in mice, and if so, which type of progenitors and what mechanism(s) are involved.

Method: We performed the prevention and regression protocols in this study. In the prevention protocol, wild-type mice were randomized to receive either pravastatin (2 mg/kg/day) or vehicle by daily gavage, and then exposed to hypoxia (10% O2) for 5 weeks in a hypoxic chamber. In the regression protocol, mice were exposed to hypoxia for 3 weeks and then received pravastatin or vehicle for additional 2 weeks in a hypoxic chamber.

Results: Chronic hypoxia increased plasma levels of SDF-1 (69 ± 12.6 to 1446 ± 515 pg/ml, P<0.01, n =11–16) and mobilization of CXCR4+/ VEGFR2+/c-kit+cells (0.02 ± 0.04 to 0.18 ± 0.06 %, P<0.01, n =5) into the pulmonary artery adventitia in vivo, both of which were significantly suppressed by pravastatin treatment in the prevention protocol (SDF-1; 1446 ± 515 vs. 826 ± 270 pg/ml, P = 0.01, n =11–16, CXCR4+/ VEGFR2+/c-kit+cells; 0.18 ± 0.06 vs. 0.05 ± 0.02 %, P<0.01, n=5), although SDF-1 levels in the lung tissue were unaltered by pravastatin. The expressions of intercellular adhesion molecule-1 (ICAM-1) and its ligand, CD18 (β2-integrin), were also enhanced by hypoxia and suppressed by pravastatin. We confirmed that pravastatin ameliorated PAH in mice in the prevention protocol. Conversely, in the regression protocol, pravastatin treatment for 2 weeks did not decrease the SDF-1 levels in the plasma or the lung tissue, or the number of circulating CXCR4+/VEGFR2+/c-kit+ cells in the peripheral blood. Further, pravastatin for 2 weeks did not ameliorate PAH in the regression protocol.

Conclusion: These results suggest that pravastatin ameliorates hypoxia-induced PAH through suppression of SDF-1/CXCR4 and ICAM-1/CD18 pathways with a resultant reduction in the mobilization and homing of BM-derived progenitor cells.